Molecular Mechanism of the Early Stage of Amyloidogenic Hexapeptides (NFGAIL) Aggregation
Molecular Mechanism of the Early Stage of Amyloidogenic Hexapeptides (NFGAIL) Aggregation
复制标题
淀粉样变性六肽（NFGAIL）聚集早期的分子机制
DOI：
10.1088/0253-6102/60/4/22
复制
发表时间：
2013-10
影响因子：
3.1
通讯作者：
修鹏
中科院分区：
文献类型：
--
作者：
修鹏
多肽/蛋白质聚集可引起许多人类疾病的病理状况。在聚集的早期阶段形成的小的部分有序的低聚物，而不是成熟的原纤维，被认为是活细胞的主要毒性物质。因此，了解早期聚集的途径和潜在的物理机制对预防和治疗这些蛋白质功能性疾病具有重要意义。本文采用全原子分子动力学模拟研究了四种NFGAIL六肽的聚集（NFGAIL肽是人胰岛淀粉样多肽的核心片段，具有与全长多肽相似的聚集动力学）。我们观察到，水中的肽单体主要采用非结构盘状构型；随机放置在水中的四种多肽通过二聚化或三聚化自发聚集成部分有序的低聚物（β-片），以二聚化为主。同时观察到平行和反平行的β片。疏水相互作用驱动最初的多肽结合，随后的构象波动促进多肽主链上悬垂的氢位点之间形成更多的氢键。
Peptides/proteins aggregation can give rise to pathological conditions of many human diseases. Small partially ordered oligomers formed in the early stage of aggregation, rather than mature fibrils, are thought to be the main toxicity agent for the living cell. Thus, understanding the pathway and the underlying physical mechanism in the early stage of aggregation is very important for prevention and treatment of these protein functional diseases. Herein we use all-atom molecular dynamics simulations to study the aggregation of four NFGAIL hexapeptides (NFGAIL peptide is a core segment of human islet amyloid polypeptide and exhibits similar aggregation kinetics as the full-length polypeptide). We observe that the peptide monomers in water mainly adopt non-structural coil configurations; the four peptides which are randomly placed in water aggregate spontaneously to partially ordered oligomer (β-sheets) through dimerization or trimerization, with the dimerization predominated. Both parallel and anti-parallel β-sheets are observed. The hydrophobic interactions drive the initial peptides associations, and the subsequent conformational fluctuations promote the formation of more hydrogen bonds between the dangling hydrogen sites in the main chains of peptides.
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影响因子：
13.8
作者：
Dobson, CM
通讯作者：
Dobson, CM
影响因子：
15
作者：
Madine, Jillian;Jack, Edward;Middleton, David A.
通讯作者：
Middleton, David A.
影响因子：
16.6
作者：
Nielsen, Jakob T.;Bjerring, Morten;Nielsen, Niels C.
通讯作者：
Nielsen, Niels C.
DOI：
10.1073/pnas.96.7.3590
发表时间：
1999-03-30
影响因子：
11.1
作者：
Chiti, F;Webster, P;Dobson, CM
通讯作者：
Dobson, CM
影响因子：
5.6
作者：
Pastor, M. Teresa;Kuemmerer, Nico;Serrano, Luis
通讯作者：
Serrano, Luis